Phlebological Review 1/2017 by Termedia sp. z o.o.

ISSN 1232-7174

2017; Vol. 25, 1

Official Journal of the Polish Society of Phlebology

SKRÓCONA INFORMACJA O PRODUKCIE LECZNICZYM: Hirudoid® 0,3 g/100 g maść, Hirudoid® 0,3 g/100 g żel. Skład jakościowy i ilościowy: 100 g maści/żelu zawiera: 0,3 g/100 g polisiarczanu mukopolisacharydowego co odpowiada 25 000 j. (jednostki ustalone na podstawie oznaczenia APTT). Pełen wykaz substancji pomocniczych patrz pkt. 6.1 ChPL. Wskazania do stosowania: do stosowania miejscowego na skórę w przypadku: tępych urazów z krwiakami lub bez krwiaków, zapalenia żył powierzchownych, których nie można leczyć opatrunkiem uciskowym. Dawkowanie i sposób podawania: nakładać 2 do 3 razy na dobę na miejsca zmienione chorobowo lub jeśli zachodzi potrzeba, częściej. W zależności od wielkości leczonej powierzchni zazwyczaj wystarcza nałożenie od 3 do 5 cm maści/żelu. Produkt leczniczy należy wmasować w miejsca zmienione chorobowo. W przypadku bolesnego zapalenia, maść/żel należy delikatnie rozprowadzić na miejscach chorobowo zmienionych. Hirudoid® maść może być używany jako opatrunek z maści. Leczeniem pierwszego rzutu w przypadku zapalenia żył powierzchownych kończyn dolnych jest zastosowanie opatrunku uciskowego. Nie należy stosować produktu leczniczego Hirudoid® żel pod opatrunek. Należy unikać kontaktu produktu leczniczego z oczami, błonami śluzowymi, otwartymi ranami a także uszkodzoną skórą. W przypadku tępych urazów leczenie zwykle trwa do 10 dni, a w przypadku zapalenia żył powierzchownych od 1 do 2 tygodni. Hirudoid® może być również stosowany do fono- i jonoforezy. Podczas jonoforezy podawany jest pod katodę. Przeciwwskazania: nadwrażliwość na polisiarczan mukopolisacharydowy, 4-hydroksybenzoesan metylu (Hirudoid® maść), 4-hydroksybenzoesan propylu (Hirudoid® maść) lub na którąkolwiek substancję pomocniczą. Nie należy nakładać maści/żelu na otwarte rany i uszkodzoną skórę. Specjalne ostrzeżenia i środki ostrożności dotyczące stosowania: substancje pomocnicze: glikol polipropylenowy, alkohol cetostearylowy, alkohol mistrylowy mogą powodować podrażnienie skóry. Działania niepożądane: zaburzenia skóry i tkanki podskórnej: (bardzo rzadko) miejscowe reakcje nadwrażliwości, takie jak zaczerwienienie skóry, które zazwyczaj przemijają szybko po zaprzestaniu stosowania produktu leczniczego. Dodatkowo Hirudoid® maść: zaburzenia układu immunologicznego: 4-hydroksybenzoesan metylu i propylu mogą powodować reakcje alergiczne. Kategoria dostępności: produkt leczniczy wydawany bez przepisu lekarza – OTC. Podmiot odpowiedzialny: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, Niemcy. Numer pozwolenia na dopuszczenie do obrotu: R/0977 (Hirudoid® maść); R/0978 (Hirudoid® żel) wydane przez Ministra Zdrowia. STADA Poland Sp. z o.o., Al. 3 Maja 6, 05-501 Piaseczno Tel. +48 22 737 79 20, Fax +48 22 750 38 82

HIR/55/04.07.17

Te w n raz opa owym kow aniu !

Official Journal of the Polish Society of Phlebology

Founded in 1993 by Dr Tomasz Drążkiewicz Official Journal of the Polish Society of Phlebology

EDITORIAL STAFF Editor-in-Chief Honorary Editor-in-Chief Associate Editor

Marian Simka (Poland) Tomasz Drążkiewicz (Poland) Zbigniew Rybak (Poland)

Editorial Office

Phlebological Review Editorial Office ul. Kleeberga 2, 61-615 Poznań phone/fax: +48 61 822 77 81 e-mail: phlebologicalreview@termedia.pl

Deputy Editors

Zbigniew Krasiński (Poland) Tomasz Urbanek (Poland) Tomasz Zubilewicz (Poland)

Section Editors

Biophysics in phlebology Fausto Passariello (Italy)

Endovascular treatment Marzia Lugli (Italy)

Laser & RF treatment Uldis Maurins (Latvia)

Leg ulcers & chronic wounds Zbigniew Rybak (Poland)

Lymphatic disorders Waldemar Olszewski (Poland)

MR imaging E. Mark Haacke (USA)

Thromboembolic disorders Evi Kalodiki (UK)

Ultrasonography Paolo Zamboni (Italy)

Vascular malformations Byung-Boong Lee (USA)

Venous disorders of the central nervous system Stefano Bastianello (Italy)

Venous & lymphatic disorders in tropical countries Surgical treatment of varicose veins Malay Patel (India) Arkadiusz Jawień (Poland) Dermatological disorders & Cosmetic treatment in phlebology Eberhard Rabe (Germany)

Sclerotherapy Alessandro Frullini (Italy) Compression therapy Giovanni Mosti (Italy) Language editor

Timothy Alexander (English)

Statistics editor

Małgorzata Misztal

Editorial Board

R. Adamiec (Poland), A. Cavezzi (Italy), L. Cierpka (Poland), A. Dorobisz (Poland), M. Drążkiewicz (Poland), Ł. Dzieciuchowicz (Poland), B. Eklöf (USA), M. Gabriel (Poland), S. Głowiński (Poland), P. Gutowski (Poland), T. Jargiełło (Poland), J. Kłoczko (Poland), W. Kostewicz (Poland), M. Kucharzewski (Poland), W. Kuczmik (Poland), Z. Mackiewicz (Poland), G. Madycki (Poland), W. Majewski (Poland), M. Maruszyński (Poland), S. Molski (Poland), M. Motyka (Poland), G. Oszkinis (Poland), R. Niżankowski (Poland), M. Pardela (Poland), F. Pukacki (Poland), J. Sadowski (Poland), S. Sajdak (Poland), A. Sieroń (Poland), M. Skórski (Poland), R. Staniszewski (Poland), W. Staszkiewicz (Poland), P. Szopiński (Poland), M. Szostek (Poland), P. Szyber (Poland), W. Tomkowski (Poland), A. Undas (Poland), Z. Várady (Germany), J. Windyga (Poland), W. Witkiewicz (Poland), M. Zaniewski (Poland), K. Ziaja (Poland)

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CONTENTS 1/2017

REVIEW PAPER

The clinical efficacy of Ruscus aculeatus extract: is there enough evidence to update the pharmacotherapy guidelines for chronic venous disease?

Tomasz Urbanek

ORIGINAL PAPER

Tumescent-assisted echosclerotherapy (TAES) in the treatment of great saphenous vein incompetence Piotr Hawro, Tomasz Urbanek, Wojciech Mikusek

CASE REPORT

Endovascular mechanical thrombectomy of the inferior vena cava and iliac veins with the use of Aspirex®S device in a paediatric patient

Paweł Latacz, Marian Simka, Tadeusz Popiela, Krzysztof Kobylarz, Janusz Skalski LETTER TO EDITOR

CCSVI in multiple sclerosis: is it the end? Alessandro Rasman

EDITORIAL

Still more controversies surrounding chronic cerebrospinal venous insufficiency Marian Simka

In this issue… Dear Colleagues and Friends, In this issue of the Phlebological Review you can find review paper on clinical efficacy of Ruscus aesculatus extract. I hope that this article will give you additional information on this pharmaceutical agent. Then there is an interesting report on tumescent-assisted foam sclerotherapy and technical note on endovascular mechanical thrombectomy for thrombotic occlusion of inferior vena cava in a child. Finally, you can find letter to the Editors regarding recently published results of the Brave Dreams clinical trial (a study aimed at evaluation of clinical efficacy of endovascular angioplasty of jugular veins for the treatment of multiple sclerosis) and editorial commentary on the same paper. I hope you enjoy your read. Sincerely, Marian Simka, MD PhD Editor-in-Chief

THE CLINICAL EFFICACY OF RUSCUS ACULEATUS EXTRACT: IS THERE ENOUGH EVIDENCE TO UPDATE THE PHARMACOTHERAPY GUIDELINES FOR CHRONIC VENOUS DISEASE? Tomasz Urbanek

REVIEW PAPER

Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland European Centre of Phleblogy, Katowice, Poland

Submitted: 18.08.2017 Accepted: 28.09.2017

ABSTRACT

The wide range of clinical presentations and patient complaints related to chronic venous disease often require complex treatments based on lifestyle modification, the use of compression stockings, pharmacotherapy, and/or surgical or other minimally invasive treatments. According to most available guidelines, the main indication for pharmacotherapy in patients with chronic venous disease is the presence of symptoms related to venous hypertension, including leg pain and heaviness. Additional patient complaints that are indicators for venotrophic pharmacological treatment include leg edema and venous leg ulcers. Despite these suggested indications, the clinical evidence for the benefit of many available drugs remains questionable. The paper presents an overview of the available literature on Ruscus aculeatus extract and drugs containing Ruscus extract. The current literature and a recent systematic review and meta-analysis confirm the use of Ruscus aculeatus extract as a phlebotropic drug with evidence-based confirmation of its positive effects on complaints related to chronic venous disease. The variety of possibilities for the pharmacological treatment of chronic venous disease enables pharmacological intervention using various compounds that address different mechanisms of chronic venous disease-related pathology. The current evidence concerning Ruscus aculeatus as a component of combined treatment (with hesperidin methyl chalcone and ascorbic acid) suggests the need to upgrade the position of this drug in the current CVD pharmacotherapy guidelines.

Phlebological Review 2017; 25, 1: 75–80 DOI: https://doi.org/10.5114/pr.2017.70594

ADDRESS FOR CORRESPONDENCE Tomasz Urbanek European Centre of Phleblogy Fabryczna 13 D 40-635 Katowice, Poland e-mail: urbanek.tom@interia.pl

Key words: Ruscus aculeatus extract, chronic venous disease, clinical efficacy, pharmacotherapy.

INTRODUCTION Understanding the pathogenesis of chronic venous disease (CVD) and the clinical consequences of venous hypertension has motivated the search for successful treatments for this condition [1, 2]. The wide range of clinical presentations and patient complaints related to CVD often require complex treatments based on lifestyle modification, the use of compression stockings, pharmacotherapy, and/or surgical or other minimally invasive treatments [2]. Pharmacotherapy is an important component of CVD treatment, and a wide range of drugs is currently available [2, 3]. Despite the number of medications used and suggested for the treatment of CVD, the evidence-based confirmation of the efficacy of many of these drugs remains

Phlebological Review 2017

limited. A lack of properly designed trials and poor quality research cause significant difficulties in creating guidelines for proper CVD treatment. According to the guidelines proposed by the European Society for Vascular Surgery (2015), venoactive drugs should be considered as a treatment option for the swelling and pain caused by chronic venous disease [4]. The guidelines proposed by the American Venous Forum and the Society for Vascular Surgery published 4 years earlier suggest the use of this group of drugs for patients with pain and swelling due to chronic venous disease in countries where these drugs are available [5]. In a document published in 2014 (Management of the Chronic Venous Disease of the Lower Limbs: Guidelines According to the Scientific Evidence), Nicolaides et al. proposed using grades to recommend the use of venoactive drugs for the “relief of symptoms associated with

Tomasz Urbanek

CVD in patients in CEAP classes C0s to C6s and those with venous edema (CEAP class C3)” [2]. Pharmacological treatment grading proposals have been suggested in 2005 in an International Consensus Statement by Ramelet et al. and in 2008 in a Guideline Document proposed by Nicolaides et al. [3, 6]. Based on previous guideline documents and the available literature, in new guidelines introduced in 2014, the quality of EBM studies was assessed as moderate for the use of micronized purified flavonoid fraction (MPFF), rutosides, red vine leaf extracts, calcium dobesilate, horse chestnut seed extract, and Ruscus extract, and the quality of evidence for the use of non-micronized or synthetic diosmins, Ginkgo biloba, and other venoactive drugs was assessed as poor [2]. Based on an evaluation of the literature, a strong recommendation (Grade 1B according to the GRADE system) was proposed only for MPFF, and a weak recommendation was given for the use of the other abovementioned drugs, with a grade 2B recommendation for rutosides, red vine leaf extract, calcium dobesilate, Ruscus extract and horse chestnut seed extract and a grade 2C recommendation for non-micronized or synthetic diosmins and Ginkgo biloba [2]. Ongoing research on CVD pathogenesis and new clinical data on pharmacological treatments and their efficacy change our understanding of the goals and possibilities of pharmacological treatment. From the clinical point of view, effects on vein tonus, decreased swelling due to improved lymphatic drainage and decreased permeability of microcirculatory vessel walls, endothelially protective effects, and anti-inflammatory and inflammation inhibitory effects are the primary components expected of many phlebotropic drugs [2, 3]. Despite laboratory data confirming some of these activities, the often subjective character of the reported symptoms related to CVD, as well as the variety of clinical presentations, cause difficulties when attempting to objectively document the positive clinical effects of a particular drug. As new studies aiming to find new targets for pharmacological treatment are proposed, there is an urgent need for the unification of study outcome criteria and their assessment in the field of CVD research. Many currently available studies use CEAP classification as well as the VAS (visual analog scale) as bases for the evaluation of patients and disease states, but quality of life and symptom assessments are necessary for the more precise evaluation of the efficacy of pharmacological treatments. The use of more complex complaint-oriented scales including the VCSS (Venous Clinical Severity Score) or a dedicated quality of life evaluation such as CIVIQ or VEINES-QOL/ Sym questionnaires has been proposed [2, 7]. In this context, when searching for evidence-based justifications for the use of a particular venotonic agent, the potential role of properly performed studies should be emphasized.

RUSCUS ACULEATUS EXTRACT AND RELATED COMPOUNDS: LABORATORY RESEARCH AND CLINICAL ACTIVITY Ruscus aculeatus extract contains two major saponins: ruskogenin and neuroruskogenin. According to previous studies, the extract contains other saponins (including ruscin and ruscoside), many of which have described anticancer activities [8, 9]. Along with saponins, Ruscus aculeatus extract contains flavonoids, sterols (sitosterol, stigmasterol, and kempesterol), tyramine, coumarin, triterpens, lignoceric acid, glycolic acid, and benzofuranes [10-14]. Ruscus aculeatus extract has been used for many years to decrease sensations of leg heaviness and leg swelling. Among its confirmed activities, one of the major effects of Ruscus extract is the vasoconstrictive activity related to α-1 and α-2 receptor agonism in the vessel wall and the release of norepinephrine from adrenergic nerve endings [15-18]. Recently, new pathways of Ruscus extract activity have been discovered, suggesting a role for muscarinic receptor agonism. Acethylocholine muscarinic and nicotinic receptors are responsible for many different activities at the molecular and tissue levels, and muscarinic receptors are present on endothelial cells. As documented by Bouskela, muscarinic receptor agonism (expressed by Ruscus extract compounds) is at least partially responsible for venule vasoconstriction [19]. According to previous studies, Ruscus extract has effects not only on veins but also on the lymphatic and capillary vessels [15]. Various mechanisms for the activity of Ruscus extract in protecting microcirculation have been suggested, including vessel vasoconstriction leading to decreased venous hypertension and local protective activity related to endothelial cell protection and anti-inflammatory properties [15-17]. An important benefit of the administration of Ruscus aculeatus extract is the inhibition of histamine-induced increased vessel wall permeability [15, 20]. Ruscus extract also affects the early phase of inflammatory reactions, leading to the decreased rolling and adherence of leucocytes to the venous wall. According to recent research, both of the abovementioned processes are at least partially controlled by the muscarinic receptor pathway [15, 19]. In previous studies, the anti-inflammatory properties of Ruscus extract were also explained by an effect on the activation of adhesive molecule (ICAM-1) expression, and a role for Ruscus extract in the action of anti-elastase on decreased vessel wall permeability was suggested [21, 22]. Vasoconstrictive Ruscus activity appears to be hormone dependent; in a study by Miller et al., venous vasoconstriction increases in the presence of increased progesterone levels [23]. The benefits of Ruscus extract have also been documented in the lymphatic system and in lymphedema patients [15]. Among the suggested mechanisms for these benefits, along with the effect of Ruscus on decreased vessel

Phlebological Review 2017

The clinical efficacy of Ruscus aculeatus extract: is there enough evidence to update the pharmacotherapy guidelines for chronic venous disease?

permeability, lymph vessel constriction and increased veno-lymphatic return have been suggested [24, 25]. Concerning the clinical efficacy of Ruscus extract, several studies have examined Ruscus aculeatus extract as an active compound of a therapeutic regimen, but few studies focus on Ruscus extract as a unique pharmacological treatment. In a randomized, placebo controlled study performed on a group of 148 patients with chronic venous disease (using solid Ruscus extract only) Vanscheidt (2002) evaluated the results of Ruscus aculeatus extract administration (in capsules containing 4.5 mg of pure roscogenin administered twice daily) over 12 weeks. The primary endpoint of the study was decreased foot and ankle volume. Secondary parameters were changes in the circumference of the lower leg and ankle, changes in subjective symptoms and quality of life, overall efficacy and tolerability, and safety parameters. The administration of Ruscus aculeatus extract resulted in significant differences between the treatment groups (Ruscus extract capsules vs. placebo) in leg volume as well as changes in ankle and leg circumferences after 8 and 12 weeks. Simultaneously, improvements in subjective CVD symptoms (heavy, tired legs and the sensation of tension) and their severity were observed in patients administered Ruscus aculeatus extract. A positive correlation between changes in leg volume and changes in the symptoms of heavy lower legs, the sensation of tension, and tingling sensations was documented [26].

RUSCUS ACULEATUS EXTRACT AS PART OF THE COMBINED PHARMACOLOGICAL TREATMENT OF CHRONIC VENOUS DISEASE Ruscus aculeatus extract can be used as an individual treatment or as a mixture with other venotonic substances in combination therapies. In the current classification of venoactive drugs, Ruscus aculeatus extract is considered a saponin. However, as mentioned above, Ruscus extract also contains other biologically active substances, such as flavonoids [3]. Few studies focused on CVD symptom treatment are dedicated to the administration of Ruscus extract alone. Most of the currently available evidence focuses on the evaluation of a commonly used combination of drugs consisting of Ruscus aculeatus extract, hesperidin methyl chalcone (HMC), and ascorbic acid. Trimethyl hesperidin chalcone is a derivative of the flavonoid hesperidin that exhibits various venoprotective effects including a potential influence on the decrease of vessel wall permeability and venous tone [3, 27, 28]. The number of previously performed studies as well as the growing body of evidence concerning this combined treatment allow important clinical conclusions to be drawn. The positive influence of the combined treatment (Ruscus extract + HMC + ascorbic acid) was confirmed in the laboratory and in clinical studies [15, 27, 28–30]. Sim-

Phlebological Review 2017

ilar to the activity of Ruscus extract, the combination of drugs including Ruscus has vasoconstrictive effects based not only on Ruscus activity but also on the properties of HMC [15, 17, 29]. Thebault, testing the activity of the combined treatment (Ruscus extract + HMC+ ascorbic acid; Cyclo 3 Fort, Pier Fabre, France), documented an additive vasoconstriction effect of HMC (the administration of Ruscus extract resulted in a 50% decrease in vein dilation, while the administration of HMC led to a 40% decrease in vein dilation) [30]. Jager conducted a duplex Doppler-based study dedicated to the effect of the same combined treatment (Cyclo 3 Fort) on the deep and superficial venous system and documented the presence of deep vein vasoconstriction with an increase in the flow parameters in the deep vein system of the leg after Cyclo 3 Fort administration [31]. The positive effects of the combined treatment were also confirmed at the microcirculatory level. Bouaziz et al. suggested an influence of the combined drug (Ruscus aculeatus extract, HMC, and ascorbic acid) on endothelial cell protection. In this study, Ruscus extract inhibited the hypoxia-induced activation of endothelial cells (resulting in decreased ATP content, phospholipase A2 activation, and increased neutrophil adherence to endothelial cells). According to this study, both Ruscus extract and HMC were able to reduce a hypoxia-induced decrease in ATP, and the effect of the combined treatment appears to be additive [32]. In another study, Bouskela et al. documented the influence of the abovementioned pharmacological treatment on the microvascular permeability induced by various agents in hamster cheek pouches [17]. The effect of the combined treatment (Ruscus, HMC, and ascorbic acid) on capillary wall permeability was also documented in diabetic patients [33]. Clinical plethysmographic studies have also produced interesting results. Bocccalon performed a double blind, placebo-controlled study with Ruscus extract, HMC, and ascorbic acid in 20 CVD patients and examined heat-induced vein distension and post-occlusion venous flow plethysmographically. According to the results of this study, the proposed pharmacological treatment decreased induced vein distention and improved normal vein drainage compared with the placebo group [34]. Improvements to venous tone and capillary sealing were confirmed after treatment with the combination of Ruscus extract, hesperidin methyl chalcone, and ascorbic acid in other studies [27, 28]. Rudofsky assessed venous capacity (VC) reduction and tissue volume decreases after the administration of the abovementioned treatment in healthy volunteers and documented a statistically significant decrease in both parameters [27]. In another clinical, prospective, capillaroscopy assessment-based study, in a group of 124 CVD patients treated pharmacologically for 8 weeks with the combined treatment, decreased CVD symptom severity (including heaviness, cramps, and edema) corresponded with decreased intracapil-

Tomasz Urbanek

lary fluid collection, reduced efferent loop thickening, decreased pericapillary beds, and decreased megacapillaries upon capillaroscopic examination [35]. In another recently published prospective study, the combination of Ruscus extract, HMC, and ascorbic acid was used in a group of 65 women (class C2s and C3s), and significant improvements in the plethysmographically evaluated venous refilling time correlated with improvements in functional CVD symptom severity [36]. Several other studies have documented the positive influence of combined Ruscus-based drug therapy on CVD symptom severity and on decreased leg edema [15, 37, 38]. Rieger, in a randomized, controlled, double-blind study performed in an orthostatic position, documented a significant decrease of calf and foot swelling after treatment with Ruscus extract, HMC, and ascorbic acid [37]. Cluzan treated patients with secondary lymphedema of the upper limb after breast cancer therapy with Cyclo 3 Fort or placebo and documented an arm volume reduction of 12.9% after 3 months of therapy [25]. Di Pieri, in a placebo controlled study performed in Italy with Ruscus aculeatus extract, HMC, and ascorbic acid (Cyclo 3 Fort), reported a statistically significant improvement in CVD-related symptoms [39]. Guex et al., in a study performed on Latin American patients, observed a significant decrease in CVD clinical symptom severity and a significant improvement in the quality of life in C0s-C3 CVD patients [40]. A meta-analysis of the efficacy of the combination of Ruscus extract, HMC, and ascorbic acid for the treatment of chronic venous disease patients was presented by Boyle et al. [41]. In this analysis, the results of 20 placebo controlled randomized double blind studies and 5 randomized studies against a comparison drug in patients with CVD were evaluated (the study population included 10,246 patients). The combined treatment significantly reduced the severity of pain, heaviness, cramps, and paresthesia. A reduction in the severity of leg edema and decreases in calf and ankle circumference were also observed, but these differences were not statistically significant [41]. Very few head to head comparisons of phlebotropic drugs have been performed. In 1999, a comparison of Cyclo 3 Fort and hydroxyethylrutosides in chronic venous and lymphatic incompetence was performed by Beltramino et al. [42]. In this study, the symptoms of chronic venous lymphatic insufficiency, including heavy, tired, and swollen legs or leg pain were evaluated at baseline and after 30, 60, and 90 days of treatment. In both groups, a reduction in CVD complaints was observed, which was more rapid in the group of patients administered Cyclo 3 Fort. Both groups exhibited reduced swelling, but after 90 days of treatment, this reduction was observed only in the group treated with Cyclo 3 Fort [42]. In another study, the efficacy of the combined treatment (Ruscus extract, HMC, and ascorbic acid) was compared with the administration of micronized diosmin [43]. In this randomized study of 100 patients, the reduction of symptoms (heavy

legs, cramps, breast tension, pelvic congestion, edema of the lower limbs) and reduced ankle circumference were found in both groups with equivalent efficacy, but the initial decrease in symptom severity was more rapid in patients taking a Ruscus-containing drug regimen (symptoms were evaluated when treatment began, and 15 and 60 days after the start of treatment). To summarize the available EBM-based knowledge on the efficacy of Ruscus aculeatus extract, HMC, and ascorbic acid (constituents of Cyclo 3 Fort) in improving individual venous symptoms and edema, a systematic review and meta-analysis of randomized double-blind placebo-controlled trials was recently presented by Kakkos and Allaert. [44]. This meta-analysis focused on 10 RCTs including 719 patients with CVD symptoms; the influence of pharmacological treatment with Cyclo 3 Fort on patients with leg edema was also analyzed [25, 38, 44-51]. According to the results, Ruscus extract, HMC, and ascorbic acid were statistically superior to placebo in reducing all analyzed CVD symptoms, including both global symptoms and the number of symptoms in a qualitative analysis. When analyzing individual CVD-related leg symptoms, statistically significant reductions in leg pain, heaviness, fatigue, sensations of swelling, cramps, pruritus, and paresthesia were observed. Ruscus-based therapy was also found to be superior to placebo at significantly reducing objectively estimated venous edema. Observations based on qualitative evaluations confirmed a significant reduction in global symptoms, as well as in pain and heaviness, analyzed as both continuous and categorical variables. The severity of cramps, pruritus, and paresthesia were reduced when assessed as continuous variables but not when evaluated as categorical variables. In the treatment of leg edema, Ruscus-based therapy statistically significantly reduced ankle circumference in comparison with placebo. The authors of this meta-analysis conclude that based on the high-quality evidence available, Ruscus extract-based pharmacological treatment is highly effective at reducing objectively measured leg edema (ankle circumference and leg/foot volume) as well as CVD symptoms such as leg pain, heaviness, the feeling of swelling, fatigue, cramps, pruritus, and paresthesia, as well as global symptoms and the total number of venous symptoms in patients with CVD. As mentioned above, the meta-analysis performed by Kakkos was based on the evaluation of randomized prospective trials and on the selection of high-quality trials. The conclusion of this analysis is also supported by a number of prospective observational studies and laboratory research. Ruscus aculeatus extract (especially in combined treatment with HMC and ascorbic acid) is among those drugs with high-quality evidence for their clinical efficacy in CVD treatment. As in most studies, a wide range of CVD patients was enrolled, and future studies should focus on the selection of patients with the highest clinical benefit from the implementation of pharmacological treatment.

Phlebological Review 2017

The clinical efficacy of Ruscus aculeatus extract: is there enough evidence to update the pharmacotherapy guidelines for chronic venous disease?

CONCLUSIONS The variety of possibilities for the pharmacological treatment of chronic venous disease enables pharmacological intervention using various compounds that address different mechanisms of chronic venous disease-related pathology. Despite a relatively extensive theoretical background and previous laboratory research, the clinical efficacy of pharmacological treatment requires clinical proof based on properly performed clinical studies. The current evidence concerning Ruscus aculeatus extract as a component of combined treatment (with HMC and ascorbic acid) suggests the need to upgrade the position of this drug in the current CVD pharmacotherapy guidelines. The author declares no conflict of interest.

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8. Mimaki Y., Kuroda M., Kameyama A., Yokosuka A., Sashida Y. Aculeoside B, a new bisdesmosidic spirostanol saponin from the underground parts of Ruscus aculeatus. J Nat Prod 1998; 61: 1279-1282. 9. Mimaki Y., Kuroda M., Yokosuka A., Sashida Y. A spirostanol saponin from the underground parts of Ruscus aculeatus. Phytochemistry 1999; 51: 689-692. 10. Mimaki Y., Kuroda M., Kameyama A., Yokosuka A., Sashida Y. New steroidal constituents of the underground parts of Ruscus aculeatus and their cytostatic activity on HL-60 cells. Chem Pharm Bull (Tokyo) 1998; 46: 298-303. 11. De Marino S., Festa C., Zollo F., Iorizzi M. Novel steroidal components from the underground parts of Ruscus aculeatus L. Molecules 2012; 17: 14002-14014. 12. Barbič M., Schmidt T.J., Jürgenliemk G. Novel phenyl-1-benzoxepinols from butcher’s broom (Rusci rhizoma). Chem Biodivers 2012; 9: 1077-1083. 13. Dunouau C., Bellé R., Oulad-Ali A., Anton R., David B. Triterpenes and sterols from Ruscus aculeatus. Planta Med 1996; 62: 189-190. 14. de Combarieu E., Falzoni M., Fuzzati N., Gattesco F., Giori A., Lovati M., Pace R. Identification of Ruscus steroidal saponins by HPLC-MS analysis. Fitoterapia 2002; 73: 583-596. 15. Jawien A., Bouskela E., Allaert F.A., Nicolaïdes A.N. The place of Ruscus extract, hesperidin methyl chalcone, and vitamin C in the management of chronic venous disease. Int Angiol 2017; 36: 31-41. 16. Bouskela E., Cyrino F.Z., Marcelon G. Effects of Ruscus extract on the internal diameter of arterioles and venules of the hamster cheek pouch microcirculation. J Cardiovasc Pharmacol 1993; 22: 221-224. 17. Bouskela E., Cyrino F.Z., Marcelon G. Possible mechanisms for the venular constriction elicited by Ruscus extract on hamster cheek pouch.J Cardiovasc Pharmacol 1994; 24: 165-170. 18. Berg D. Venous constriction by local administration of ruscus extract. Fortschr Med. 1990; 108: 473-476. 19. Rauly-Lestienne I., Heusler P., Cussac D., Lantoine-Adam F., de Almeida Cyrino F.Z.G., Bouskela E. Contribution of muscarinic receptors to in vitro and in vivo effects of Ruscus extract. Microvasc Res. 2017; 114: 1-11. 20. Bouskela E., Cyrino F.Z., Marcelon G. Possible mechanisms for the inhibitory effect of Ruscus extract on increased microvascular permeability induced by histamine in hamster cheek pouch. J Cardiovasc Pharmacol. 1994; 24: 281-285. 21. Facino R.M., Carini M., Stefani R., Aldini G., Saibene L. Antielastase and anti-hyaluronidase activities of saponins and sapogenins from Hedera helix, Aesculus hippocastanum, and Ruscus aculeatus: factors contributing to their efficacy in the treatment of venous insufficiency. Arch Pharm (Weinheim). 1995; 328: 720-724. 22. Huang Y.L., Kou J.P., Ma L., Song J.X., Yu B.Y. Possible mechanism of the anti-inflammatory activity of ruscogenin: role of intercellular adhesion molecule-1 and nuclear factor-kappaB. J Pharmacol Sci 2008; 108: 198-205. 23. Miller V.M., Marcelon G., Vanhoutte P.M. Progesterone augments the venoconstrictor effect of Ruscus without altering adrenergic reactivity. Phlebology 1991; 6: 261-268. 24. Marcelon G., Pouget G., Tisné-Versailles J. Effect of Ruscus on the adrenoceptors of the canine lymphatic thoracic duct. Phlebology 1988; 3, 109-112.

Tomasz Urbanek

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cyclo -3 fort versus hydroxy ethyl rutoside in chronic venous lymphatic insufcicency. Angiology. 2000; 51: 535-544. 43. Monteil Seurin J. Insuffissance veino lymphatique; étude comparative de Cyclo 3 Fort (Fabroven) versus Diosmine micronisée. Comptes Rendus de Thérapeutique et de Pharmacologie Clinique 1993; 109: 3-7. 44. Kakkos S.K., Allaert F.A. Efficacy of Ruscus extract, HMC and vitamin C, constituents of Cyclo 3 fort®, on improving individual venous symptoms and edema: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol 2017; 36: 93-106. 45. Altenkamp H. Efficacy of antivaricotic drugs can be measured objectively. Phlebologie in der Praxis 1987; 2: 9-20 46. Elbaz C., Nebot F., Reinharez D. Insuffisance veineuse des membres inférieurs étude controleé de l’action du Cyclo 3. Phlébologie 1976; 29: 77-84. 47. Le Devehat C., Lemoine A., Roux E., Cirette B., Vimeux M., Martinaggi P. Aspects clinique et hémodynamique de Cyclo 3 dans l’insuffisance veineuse. Angéiologie 1984; 3: 119-122. 48. Parrado F., Buzzi A. A study of the efficacy and tolerability of a preparation containing Ruscus aculeatus in the treatment of chronic venous insufficiency of the lower limbs. Clin Drug Investig 1999; 18: 255-61 49. Questel R., Walrant P. Bilan de l’essai randomisé Veinobiase contre placebo dans l’unsuffisance veineuse: observation de la microcirculation per capillarographie conjonctivale. Gazette Medicale de France 1983; 90: 508-14 50. Rudofsky G., Diehm C., Gruß J.D., Hartmann M., Schultz-Ehrenburg H.K., Bisler H. Chronic venous insufficiency. Treatment with Ruscus extract and trimethylhesperidin chalcone. MMW Munch Med Wochenschr 1990; 132: 205-210. 51. Sentou Y., Bernard-Fernier M.F., Demarez J.P., Laurent D., Cauquil J. Symptomatologie et pléthysmographie: Parallélisme des resultants obtenus lors d’un traitement par Cyclo 3 de patientes porteuses d’une insuffisance neineuse chronique (étude en double insu contre placebo). Gazette Medicale 1985; 92: 73-77.

Phlebological Review 2017

TUMESCENT-ASSISTED ECHOSCLEROTHERAPY (TAES) IN THE TREATMENT OF GREAT SAPHENOUS VEIN INCOMPETENCE Piotr Hawro1,2, Tomasz Urbanek2,3, Wojciech Mikusek1,2

ORIGINAL PAPER

European Centre of Phlebology, Angelius Hospital, Katowice, Poland Minimally Invasive Phlebology Centre AVIMED, Bytom, Poland 3 Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland

Submitted: 3.12.2017 Accepted: 14.12.2017

1 2

ABSTRACT

Objectives: Despite encouraging results of saphenous vein sclerotherapy this method is not free of potential complications and does not guarantee a 100% rate of occlusion. In this paper, the author’s own experiences with catheter-directed, tumescent solution-supported echo-guided foam sclerotherapy of the saphenous vein are presented. Material and methods: Thirty-four incompetent great saphenous veins were treated with foam sclerotherapy involving the use of long catheters and perivenous tumescent solution injection prior to foam administration. The mean length of incompetent saphenous veins was 25.5cm (range 14-39 cm). The diameters of the proximal part of the saphenous veins ranged from 5.0 to 15.0 mm. In 25 patients (71.4%), primary varicose veins were diagnosed, and in other patients either post–surgical (recurrent) or post-thrombotic saphenous veins were treated. Results: At 30-day follow up total occlusion of the entire segment of treated vein was achieved in 79.4% of cases. In one case the vein was not occluded, and in 6 patients (17.6%) a partial occlusion was revealed. In the group of 6 patients with partial vein occlusion, a repeated sclerotherapy with the use of a short catheter and ultrasound guided puncture was performed. 6 and 12 months after the procedure, 32 out of 34 obliterated veins (94.1%) remained fully occluded. The mean foam volume used for saphenous vein obliteration was 2.6 ml. No serious adverse events were reported. Conclusions: Tumescent-assisted echo-guided foam sclerotherapy is a safe and clinically effective method of saphenous vein obliteration, particularly for veins with no history of a previous thrombosis or surgical treatment.

Phlebological Review 2017; 25, 1: 81–86 DOI: https://doi.org/10.5114/pr.2017.72537

ADDRESS FOR CORRESPONDENCE Tomasz Urbanek European Centre of Phleblogy Fabryczna 13 D 40-635 Katowice, Poland e-mail: urbanek.tom@interia.pl

Key words: foam sclerotherapy, tumescent anesthesia, varicose vein treatment.

INTRODUCTION Progress related to the diagnostic and minimally invasive treatment of chronic venous diseases has led to significant improvement of the care of these patients. One of the most important steps towards modern phlebological treatment was the introduction of duplex Doppler diagnostic to the daily clinical practice [1]. Another factor that should be mentioned is sclerotherapy, which is currently used for the treatment of a wide range of venous pathologies [2]. Further progress basing on the implementation of endoluminal thermal and non-thermal ablation methods has increased the treatment possibilities and their efficacies. Foam sclerotherapy was firstly described by S. McAus land in 1939 [3]. Another researcher who described the use of foam sclerotherapy for the treatment of reticular varicose veins was Robert Rowden Foote [4]. In 1956, Peter Fluckiger described the possibility of mechanical

Phlebological Review 2017

movement of the foam from the place of injection via manual compression and manipulation [5]. Over the years the method of foam production has been improved and established. Currently, the most commonly used method of foam production is the technique proposed by Lorenzo Tessari [6]. According to this method, two syringes are directly connected through three-way stopcock or a double syringe connector (DSS method). The proposed ratio of gas to liquid sclerosant ranges from 4 : 1 to 5 : 1, and various gas types have been investigated (air, CO2/O2 mixtures and CO2). The implementation of ultrasound (US) examination not only improved diagnoses, but also led to clinical application of US examinations during sclerotherapy, including the US-guided foam sclerotherapy procedure. In 1968, Siegel from Philadelphia for the first time described continuous wave (CW) Doppler US for diagnosing venous system of the lower leg [7]. B mode US examination combined with CV Doppler for diagnosing the venous system

Piotr Hawro, Tomasz Urbanek, Wojciech Mikusek

of lower extremities was proposed for the first time by Day in 1976 [8]. In 1977 Franceschi documented the effect of calf compression and deep inspiration and expiration on venous flow in standing and recumbent positions, as well as the effect of Valsalva manoeuvre, and described the exploration of the veins with Doppler in normal subjects and varicose vein patients [9]. In 1982, Steve Talbot used Doppler US to confirm the role of Valsalva manoeuvre in the stimulation of venous flow changes in healthy veins. Talbot also confirmed the possibility of occlusion of venous lumen using a compression with sonographic probe [10]. In 1984 Effeney suggested that unchanged diameter of the vein during Valsalva manoeuvre is suggestive of the presence of thrombus inside venous lumen. In 1986, Ragavendra described clinical implementation of US-controlled compression test for the diagnosis of deep vein thrombosis [11]. In the same year Michel Schadeck published his experience with the use of US during foam sclerotherapy [12]. Sclerotherapy through a long catheter (with a liquid sclerosant) was presented for the first time by A. Gattoduring at the UIP World Congress in 1989 in Strasburg [13]. US-guided catheter-directed sclerotherapy was described in 1992 by Louis Grondin [14], and in 1995 Robert and Robert described the use of a dedicated catheter during the US-guided liquid sclerotherapy [15]. In 1997, the extended long-line echosclerotherapy method was proposed by Kurosh Parsi. In this method, following the cannulation of the saphenous vein, the tip of catheter is positioned 5 cm below the saphenofemoral junction, the leg is elevated at the angle of 45˚, and liquid sclerosant is injected. The injection of the sclerosing agent causes visible turbulence on B-mode US, and also leads to an increased resistance against external compression of the vein wall following the procedure. In further studies, the catheter-directed US-guided sclerotherapy method was continuously modified and improved. Basing on experiences of Min and Navarro, the Seldinger method for venous access was proposed [16]. The implementation of perivenous tumescent infiltration aimed at external compression of the vein was firstly proposed by Thibault [17]. Milleret presented a similar technique augmented with an application of the Esmarck cuff in order to empty the vein prior to injection of the sclerosant [18]. The natural course of this research led to improved technique of sclerotherapy, such as foam sclerotherapy and the use of dedicated catheters, including balloon occlusive catheters [19, 20]. In recent years, many papers have confirmed the simplicity and safety of catheter-guided sclerotherapy [21-23]. Cavezzi, searching for better results of foam sclerotherapy, described several sclerosing agent/gas mixtures [24]. The method of sclerotherapy through multiple short catheters has also been proposed [25, 26]. In addition, Frullini presented the LAFOS method, basing on application of the holmium laser, which is used in order to shrink the vein before sclerotherapy [27]. A recent important modification of sclerotherapy com-

prises mechanochemical endovenous ablation (MOCA) [28]. In this method mechanical irritation of venous wall results in its shrinkage, which enables administration of a reduced volume of sclerosing agent and eliminates the need for tumescent anaesthesia. The newest non-tumescent method for vein ablation comprises vein closure by intravenous application of a glue (cyanoacrylate) [29]. According to previous publications and authors’ own experience, foam sclerotherapy can be used as a single treatment method, or in combination with surgical or endoluminal saphenous vein ablation [30-32]. In many cases foam sclerotherapy can be successfully used for complex treatments of pathologies of the entire superficial vein system, including obliteration of large veins and sclerotherapy of varicose veins. Regarding foam sclerotherapy treatment (including saphenous vein obliteration), both efficacy and safety have to be taken into consideration, especially if long vein segments or large veins need be ablated. The proper concentration of sclerosing agent and proper volume of injected foam are important factors that potentially can influence final outcome. According to current sclerotherapy guidelines (European Guidelines on Sclerotherapy), the maximum foam volume applied during one session should not exceed 10 ml, but this volume is not always sufficient to ablate long or large veins [33]. Alternatively to the use of MOCA, it is possible to administer tumescent solution around the treated vein in order to decrease volume of foam, which is needed for successful sclerotherapy. Potentially, an external compression along the entire vein can improve contact of foam with the venous wall (due to blood removal) and protect the sclerosant from being deactivated by blood compounds [34, 35]. In this paper, the authors present their own experiences with US-guided, catheter-directed, tumescent supported foam obliteration (TAES) of incompetent saphenous veins.

MATERIAL AND METHODS Thirty-four legs of 34 patients with incompetence of the great saphenous veins were treated with TAES and prospectively evaluated. The study was based on the prospective, non-interventional observation of the group of patients, who were managed using a standard treatment and follow up protocol applied in the European Centre of Phlebology in Katowice. All patients approved and signed the informed consent for standard treatment protocol and follow up. Data were prospectively and anonymously collected, without any integration into the patient treatment. The group consisted of 26 female patients and 8 men. Mean age of patients was 47 years (19-72 years). Primary varicose veins were diagnosed in 25 patients (71.4%). Other patients presented with recurrent varicose veins (5 cases) or varicose veins associated with a history of superficial thrombosis (4 cases). Mean length of incompetent

Phlebological Review 2017

Tumescent-assisted echosclerotherapy (TAES) in the treatment of great saphenous vein incompetence

saphenous vein was 25.5 cm (range: 14 to 39 cm). Diameters of proximal parts of the saphenous veins ranged from 5.0 to 15.0 mm (mean: 6.97 mm), and distal diameters (at the lowest point of reflux) ranged from 5 to 8 mm (mean: 5.65 mm). A significant percentage of patients presented with concomitant morbidities (Table 1). In addition, 4 female patients received hormonal replacement therapy. Duplex Doppler US examinations of the venous system were performed in all patients. Majority of patient presented with class C2 and C3 of the CEAP classification and only a few with more advanced disease (Fig. 1). Exclusion criteria comprised: active venous thromboembolism, known allergic reactions to polidocanol or lidocaine, previous endovenous thermal or non-thermal ablation of varicose veins, known arteriovenous shunts, pregnancy, obstructive changes or occlusions in the deep venous system, significant leg ischemia (ABI < 0.8), recent (< 12 months) superficial vein thrombosis, known contraindications to compression therapy.

Table 1. Concomitant diseases No of patients.

Ischaemic heart disease

35.3

Arterial hypertension

44.1

Diabetes mellitus

11.8

Obesity

23.5

Osteoarticular degenerative disease

23.5

C5 C6 3% 3% C4 9%

C2 50%

Procedure description The treatments were performed under US guidance. The vein puncture was localised in the lowest point of truncal reflux, and after administration of local anaesthesia (1% lidocaine), vein puncture with an 18-G needle was performed. A 0.035” guidewire was introduced and a 4F straight catheter was inserted into the vein lumen. The tip of catheter was placed 3 cm below the saphenofemoral junction, and the guidewire was removed. The position of the tip of catheter was controlled using US. After catheter positioning, the tumescent solution was injected into the perivenous space. The following tumescent solution mixture was used: lidocaine – 1 g/l; epinephrine – 1 mg/l; 8.4% sodium bicarbonate – 10 mEq/l and 0.9% NaCl up to the volume of 1000 ml. The pump was used for injection of tumescent solution and 10 mL of solution per 1 cm of the treated vein was injected (the injection of tumescent solution was US-controlled to confirm complete compression of the vein around the catheter). After compressing the vein and the check of the position of catheter tip, 3% polidocanol foam was injected. The foam was prepared according to the Tessari method. The velocity of the injection depended on US control. During the injection the traction of the catheter was US-controlled in order to fill the target vein lumen with foam but not moving it (except for single foam bubbles) into the deep vein system. The foam volume of each procedure was recorded. After foam injection and catheter removal, access area was covered with sterile dressings and class 2 thigh compression stocking was worn, with recommendation of applying stockings for 4 weeks. Then the patients were mobilised and discharged. At follow-ups, which were performed 1, 6, 12 and 18 months after sclerotherapy, patients were assessed clinically and with the use of US. Total occlusion was defined as an occlusion of the entire

Phlebological Review 2017

C3 35%

Fig. 1. C class of the CEAP classification in the treated group length of target vein from the access area to the saphenofemoral junction. Partial occlusion was defined as a lack of full occlusion of the entire length of the treated venous segment (a presence of patent segments between the occluded proximal or distal parts of the treated vein). In all cases the management of non-saphenous varicose veins with sclerotherapy was postponed until occlusion of the saphenous vein was confirmed at a follow up. The Statistica 10 software package was used for statistical analysis. In order to identify factors that potentially were responsible for unsuccessful treatment we applied the multiple regression analysis.

RESULTS We injected 1.5-4 ml of 3% polidocanol during sclerotherapy; mean volume of foam was 2.6 ml. No serious advert events, including neurological or ophthalmological symptoms potentially related to the administration of foam, were reported. No symptomatic or asymptomatic DVT were diagnosed at follow up. One month after the procedure a complete occlusion of the entire segment of target vein was confirmed in 79.4% of cases (27 out of 34 veins). In one case (2.9%), the vein was still patent and partial occlusion was observed in

Piotr Hawro, Tomasz Urbanek, Wojciech Mikusek

100 90 80 70 60 50 40 30 20 10 0

1 month after 6 month after 12 month after 18 month after TAES TAES TAES TAES Full occlusion Partial occlusion Non occluded vein

Fig. 2. Success rate 1, 6, 12 and 18 months after TAES of the great saphenous vein (34 treated veins) 6 patients (17.6%). In the group of 6 patients with partial occlusion, 1 month after the first intervention we performed another foam sclerotherapy, using a direct puncture of the vein under US control. For this purpose we used 1-3 mL of 3% polidocanol (mean: 2.33 mL). Out of these patients, 5 developed full obliteration of the target vein, and 1 patient only partial occlusion, with a 12-cm long segment of non-occluded vein. One patient with completely failed first session of sclerotherapy did not consent for further treatment with this method. At follow ups 6 and 12 months after the procedure, 32 out of 34 obliterated veins (94.1%) remained fully occluded. There were 2 additional cases of partial recanalisation at 18-month follow up (Fig. 2). We also analysed patients with non-occluded and partially occluded veins after the first session of sclerotherapy. The patient with failed sclerotherapy had a history of previous thrombosis of the saphenous vein. In the group of patients with partial recanalisation (6 individuals), 2 of them presented with recurrent varicosities after surgical treatment, while 2 patients had a history of thrombosis of the saphenous vein. Technical success of sclerotherapy after 1 session of treatment in patients without a history of previous saphenous vein surgery or thrombosis was 92%. Other clinical factors evaluated by means of multivariate analysis, such as patient’s age, duration of the disease, C class of the CEAP classification, length of the target vein and its diameter were not found to be statistically significant. We also evaluated the cost of procedure. An average cost of medications and disposables was 25 euro per patient.

DISCUSSION According to the results of our study a high efficacy and safety of TAES, combined with a low cost of this procedure, justifies its use as the cost-effective method for the treatment of the saphenous vein incompetence.

The concept of application of tumescent solution perivenously is currently well known and widely used during treatment of patients managed with thermal ablations. As has been previously mentioned, the use of tumescent solution was also proposed to augment sclerotherapy [34, 35]. A fluid injected perivenously compresses the vein, removes blood from its lumen and leads to significant shrinking of the target vein that allows a reduction of foam volume. These factors, at least theoretically, can result in a higher efficacy and safety of the treatment. Still, high quality studies confirming efficacy and safety of TAES in clinical practice have not yet been released [17, 30, 34, 35]. Sclerotherapy is a standard phlebological procedure [33] and combined treatment (foam sclerotherapy with the application of perivenous tumescent solution) seems to be an interesting alternative for more technically complex and more expensive methods, such as RF and EVLT. In our patient series 94.1% of the managed saphenous veins remained fully occluded at 6- and 12-month follow ups. A majority of failed treatments occurred in patients with a history of saphenous thrombosis or previous varicose vein surgery. Still, a redo sclerotherapy resulted in complete closure of target veins in most of these patients. Moreover, final results at 1-, 6- and 12-month follow ups, including reinterventions, were similar in patients with and without a history of previous thrombosis or surgery. This finding, together with a relatively low cost of the procedure (25 euro per session of TEAS) suggests that this method is an interesting alternative to more sophisticated treatment modalities, especially in patients with no history of thrombosis or surgical treatment for varicose veins [31]. A high safety of TEAS should also be emphasised. We did not observe any serious adverse events, which was potentially due to the following factors: reduced foam volume (mean volume of foam required for obliteration of the saphenous vein was 2.6 ml, and maximal volume in the case of a 39-cm long vein was 4 ml), emptying of the vein, which decreases the amount of blood inside its lumen and potentially diminished risk of foam migration related to compression of the venous lumen. At follow ups no deep venous thromboses were diagnosed, despite the fact that 8 saphenous veins were larger than 8 mm in diameter. Studies on sclerotherapy suggest that early recanalisations are related to the large diameters of the vein. This phenomenon can be explained by possible deactivation of sclerosing agent by blood present in the venous lumen [31, 33]. An application of tumescent solution leads to emptying of the vein, which together with vasoconstrictive activity of epinephrine improves final results of the treatment [29, 33, 34]. Currently only one controlled randomised study on TAES has been published. Devereux and co-workers did not demonstrate an advantage of application of tumescence solution during foam sclerotherapy of the great

Phlebological Review 2017

Tumescent-assisted echosclerotherapy (TAES) in the treatment of great saphenous vein incompetence

saphenous vein performed through a long catheter [33]. Still, some of the methods used in this study have to be challenged, particularly the fact that a 0.9% tumescent solution without epinephrine was injected, which potentially could negatively influenced final results. Epinephrine is one of the components of a standard tumescent anaesthesia. Rationale of its use is to decrease absorption of the tumescent solution and to prolong and enhance vasoconstriction of the vein. This issue was addressed by Cavezzi in the discussion on the results of the Devereux’s study [35]. Thus, we need another prospective randomised clinical trial to evaluate the actual efficacy of TAES.

CONCLUSION Tumescent-assisted echo-guided foam sclerotherapy is a safe and clinically effective method for obliteration of the saphenous vein, particularly in patients with no previous history of superficial venous thrombosis or surgical treatment of varicose veins. The author declares no conflict of interest.

References 1. Hawro P., Gabriel M., Madycki G., Kuczmik W., Urbanek T. Zalecenia dotyczące wykonywania ultrasonograficznego badania dopplerowskiego żył kończyn dolnych Polskiego Towarzystwa Chirurgii Naczyniowej i Polskiego Towarzystwa Flebologicznego. Acta Angiol 2013; 19: 99-117. 2. O’Flynn N., Vaughan M., Kelley K. Diagnosis and management of varicose veins in the legs: NICE guideline. Br J Gen Pract 2014; 64: 314-315. 3. McAusland S. The modern treatment of varicose veins. Med Press Circular 1939; 201: 404-410. 4. Foot R.R. The injection treatment. In: Foote R.R. (ed.). Varicose veins, haemorrhoids and other conditions. Lewis, London 1944: 13-44. 5. Fluckiger P. Nicht-operative retrograde Varicenverodung mit Varsylschaum. Schweiz Med Wochenschr 1956; 86: 1368-70. 6. Cavezzi A, Frullini A, Ricci S, Tessari L. Treatment of varicose veins by foam sclerotherapy: two clinical series. Phlebology 2002; 17: 13-18. 7. Sigel B., Popky G.L., Wagner D.K., Boland J.P., Mapp E.M., Feigl P. Comparison of clinical and Doppler ultrasound evaluation of confirmed lower extremity venous disease. Surgery 1968; 64: 332-338. 8. Day T.K., Fish P.J., Kakkar W. Detection of deep vein thrombosis by Doppler angiography. Br Med J 1976; 1: 618-20. 9. Franceschi C. L’investigation vasculaire par ultrasonographie Doppler. Masson edit. Paris, 1977. 10. Talbot S.R. Use of real-time imaging in identifying deep venous obstruction: a preliminary report. Bruit 1982; 7: 41-2. 11. Cronan J.J. History of Venous Ultrasound. J Ultrasound Med 2003; 22: 1143-1146. 12. Schadeck M. Doppler et Echotomographie dans la sclerose des veines saphe`nes. Phlebologie 1986; 39: 697-716.

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13. Gatto A. La sclerose de la saphene interne jusqua la crosse avec catheter (video). In: Davy A., Stemmer R. (eds.). Phlebologie. John Libbey Eurotext Ltd, 1989; 797. 14. Grondin L., Soriano J. Duplex-echosclerotherapy, the quest for the safe technique. Phlebologie. John Libbey, Paris 1992: 824-5. 15. Robert C., Robert J.L. La sclerose par echo-catheterisme. Phlebologie 1995; 48: 13-16. 16. Min R.J., Navarro L. Transcatheter duplex ultrasoundguided sclerotherapy for treatment of greater saphenous vein reflux: preliminary report. Dermatol Surg 2000; 26: 410-4. 17. Thibault P. Internal compression (peri-venous) following ultrasound guided sclerotherapy to the great and small saphenous veins. Aust NZ J Phleb 2005; 9: 29-32. 18. Milleret R., Garandeau C., Brel D., Allaert F.A. Foam sclerotherapy of the great saphenous veins via ultrasound-guided catheter in an empty vein: the alpha-technique. Phlebologie 2004; 57: 15-18. 19. Bidwai A., Beresford T., Dialynas M., Prionidis J., Panayiotopoulos Y., Bowne T.F. Balloon control of the saphenofemoral junction during foam sclerotherapy: proposed innovation. J Vasc Surg 2007; 46: 145-7. 20. Brodersen J.P. Catheter-assisted vein sclerotherapy: a new approach for sclerotherapy of the greater saphenous vein with a double-lumen balloon catheter. Dermatol Surg 2007; 33: 469-75. 21. Wildenhues B. Catheter-assisted foam sclerotherapy: a new minimally invasive method for the treatment of trunk varicosis of the long and short saphenous veins. Phlebologie 2005; 34: 165-170. 22. Hahn M., Schulz T., Junger M. Sonographically guided, transcatheter foam sclerotherapy of the great saphenous vein; medical and oeconomic aspects. Phlebologie 2007; 36: 309-312. 23. Kolbel T., Hinchliffe R.J., Lindbal B. Catheter-directed foam sclerotherapy of axial saphenous reflux: early results. Phlebology 2007; 22: 219-222 24. Cavezzi A., Tessari L. Foam sclerotherapy techniques: different gases and methods of preparation, catheter versus direct injection Phlebology 2009; 24: 247-251. 25. Jaworucka-Kaczorowska A., Jaworucki M. Echoskleroterapia piankowa przy użyciu venflonów wspomagana tumescencją w leczeniu przewlekłej niewydolności żyły odpiszczelowej. Phlebol Rev 2013; 21: 28. 26. Parsi K., Exner T., Connor D.E., Herbert A., Ma D.D.F., Joseph J.E. The lytic effects of detergent sclerosants on erythrocytes, platelets, endothelial cells and microparticles are attenuated by albumin and other plasma components in vitro. Eur J Vasc Endovasc Surg 2008; 36: 216-223. 27. Frullini A., Fortuna B. Laser assisted foam sclerotherapy (LAFOS): a new approach to the treatment of incompetent saphenous veins. Phlebologie 2013; 66: 51-54. 28. Elias S., Lam Y.L., Wittens C.H. Mechanochemical ablation: status and results. Phlebology 2013; 28 (Suppl 1): 10-14. 29. Guex J.J. Endovenous chemical (and physical) treatments for varices: what’s new? Phlebology 2014;29 (Suppl 1): 45-48. 30. Cavezzi A., Mosti G., Di Paolo S., Tessari L., Campana F., Urso S.U. Ultrasound-guided perisaphenous tumescence infiltration improves the outcomes of long catheter foam sclerotherapy combined with phlebectomy of the varicose tributaries. Veins Lymphatics 2015; 4: 4676. 31. Gohel M. Which treatments are cost-effective in the management of varicose veins? Phlebology 2013; 28 (Suppl 1): 153-7.

Piotr Hawro, Tomasz Urbanek, Wojciech Mikusek

32. Nesbitt C., Eifell R.K., Coyne P., et al. Endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus conventional surgery for great saphenous vein varices. Cochrane Database Syst Rev 2011; 10: CD005624. 33. Rabe E., Breu F.X., Cavezzi A., et al. European guidelines for sclerotherapy in chronic venous disorders. Phlebology 2014; 29: 338-354. 34. Devereux N., Recke A.L., Westermann L., Recke A., Kahle B. Catheter-directed foam sclerotherapy of great saphenous veins in combination with pre-treatment reduction of the diameter employing the principals of perivenous tumescent local anesthesia. Eur J Vasc Endovasc Surg 2014; 47: 187-195. 35. Cavezzi A., Mosti G., Di Paolo S., Tessari L., Campana F., Urso S.U. Re: catheter-directed foam sclerotherapy of great saphenous veins in combination with pre-treatment reduction of the diameter employing the principals of perivenous tumescent local anesthesia’. Eur J Vasc Endovasc Surg 2014; 48: 597.

Phlebological Review 2017

ENDOVASCULAR MECHANICAL THROMBECTOMY OF THE INFERIOR VENA CAVA AND ILIAC VEINS WITH THE USE OF ASPIREX®S DEVICE IN A PAEDIATRIC PATIENT Paweł Latacz1, Marian Simka2, Tadeusz Popiela3, Krzysztof Kobylarz4, Janusz Skalski5 Department of Neurology, Jagiellonian University Medical College, Krakow, Poland Private Healthcare Institution SANA Outpatient Department of Angiology, Pszczyna, Poland 3 Chair of Radiology, Jagiellonian University Collegium Medicum, Krakow, Poland 4 Department of Anaesthesiology and Intensive Care, University Children’s Hospital of Cracow, Krakow, Poland 5 Department of Cardiosurgery and Intensive Cardiosurgery Care, University Children’s Hospital of Cracow, Krakow, Poland 1 2

ABSTRACT

Phlegmasia cerulea dolens, which is the most severe clinical presentation of deep venous thrombosis and results from an almost complete occlusion of the major and collateral venous outflow routes from the extremity, is very rarely seen in children. Here we describe the treatment of an 11-year-old boy with Down syndrome who presented with thrombotic occlusion of the inferior vena cava and both iliac veins. We present a step-by-step technique of endovascular mechanical thrombectomy of these veins with the use of the Aspirex®S thrombectomy device. Endovascular treatment was followed by local intravenous thrombolysis. Because of recurrent thrombosis, which occurred 4 days later, endovascular thrombectomy and thrombolysis were performed again. Finally, the treatment resulted in complete restoration of patency of occluded veins. Except for a minor local bleeding in the area of vascular access, there were no adverse events associated with endovascular management in this paediatric patient.

CASE REPORT Phlebological Review 2017; 25, 1: 87–90 DOI: https://doi.org/10.5114/pr.2017.72538 Submitted: 17.07.2017 Accepted: 5.09.2017

ADDRESS FOR CORRESPONDENCE Paweł Latacz, PhD, MD Department of Neurology Jagiellonian University Medical College Botaniczna 3 31-503 Kraków, Poland e-mail: pawlat@me.com phone +48124248600

Key words: Phlegmasia cerulea dolens, endovascular mechanical thrombectomy, Aspirex.

INTRODUCTION Phlegmasia cerulea dolens, which is the most severe clinical presentation of deep venous thrombosis and results from an almost complete occlusion of the major and collateral venous outflow routes from the extremity, is very rarely seen in children [1-6]. Here we present the treatment of severe thrombosis of the inferior vena cava and deep veins of both lower extremities in an 11-yearold boy.

CASE PRESENTATION An 11-year-old male patient with Down syndrome was admitted to our hospital because of upper respiratory tract infection accompanied by high fever. After 2 days of hospital stay he was discharged with recommendation for further outpatient treatment. Still, after 5 days he was again admitted to the hospital because of swelling of both lower extremities, primarily on the left side, and also of the scrotum and penis (Fig. 1A). This severe oedema clin-

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ically manifested as phlegmasia cerulea dolens. CT angiography revealed thrombotic occlusion of the inferior vena cava (Fig. 1B) and bilateral occlusions of the external iliac and femoral veins, which on the left side was associated with thrombosis of superficial tributaries of the femoral vein. After consultation by paediatric cardiac surgeon, considering the fact that thrombotic material could not be removed surgically, the patient was managed with fibrinolytics (alteplase). However, fibrinolytic treatment was unsuccessful and the status of oedematous lower limbs deteriorated. Therefore we decided to perform percutaneous mechanical thrombectomy with the use of the Aspirex®S thrombectomy device (Straub Medical AG, Wangs, Switzerland).

INTERVENTION Firstly, under sonographic control, we cannulated the right femoral vein with a 6F Brite tip® guiding catheter (Cordis, Fremont, CA, USA). We did not cannulate the popliteal vein because it was very narrow, about 2 mm

Paweł Latacz, Marian Simka, Tadeusz Popiela, Krzysztof Kobylarz, Janusz Skalski

Fig. 1. A) Initial state of patient: large oedema of the lower limbs, scrotum and penis. B) CT angiography of the veins – visible large thrombus in distal part of the inferior vena cava (1), occlusion of the illiac veins. C) Venography of the external and common iliac vein – no flow of contrast, with a large thrombus (2). D) System of endovascular mechanical thrombectomy Aspirex advanced into the iliac veins (3). E) Venography of the partially recanalised inferior vena cava and iliac veins after the use of Aspirex (5) – visible residual 80-90% stenosis with a flow of contrast. F) Venography of the left external and common iliac veins (6) after thrombectomy with Aspirex system in diameter. Catheter angiography confirmed thrombotic occlusion of the iliac vein and the inferior vena cava (Fig. 1C). With the use of a 260-cm-long AqWireTM hydrophilic guidewire (Covidien, ev3 Endovascular, Inc., Plymouth, MN, USA) and a vertebral diagnostic catheter we navigated through the occlusion to the right atrium and then to the left subclavian vein. We introduced the 6F Aspirex®S and with the use of this device we removed thrombi from the inferior vena cava and from the right common and external iliac veins (Fig. 1D). Control angiography revealed partially recanalised inferior vena cava (Fig. 1E). Of note, there were no anatomic abnormalities of the inferior vena cava, such as aplasia, septum or a web. We continued aspiration thrombectomy of the right iliac vein and inferior vena cava, and then we cannulated the left femoral vein with the 6F/45 cm Destination® guiding sheath (Terumo, Tokyo, Japan). Through this sheath we performed thrombectomy with the Aspirex®S device of the left femoral and iliac veins. Catheter angiography demonstrated partial recanalisation of these veins (Fig. 1F). Finally, we introduced the Fountain infusion catheter (Merit Medical Systems, Inc., South Jordan, UT, USA), which is equipped with a system of gradient-sized holes enabling uniform dispersion of therapeutic agent.

Through this catheter, over the entire length of the iliac veins, alteplase was administered for 48 h (initial dose 3 mg, then 10 mg in infusion). We also administered a sub-therapeutic dose of low-molecular-weight heparin. This treatment was complicated by local bleeding (which required long compression and transfusion of blood) at the site of vascular access. After the treatment the patient improved clinically and control angiography demonstrated patent inferior vena cava and both iliac veins and partial reduction of swelling of the scrotum (Fig. 2A and 2D). Still, after 4 days both iliac veins reoccluded. We again performed aspiration thrombectomy with the Aspirex®S device (Fig. 2B and 2C), which was followed by local intravenous administration of alteplase for 72 h. There were no complications associated with the second treatment. The treatment with alteplase was then followed by administration of a low-molecular-weight heparin. Although there were still residual thrombi and stenoses of the iliac veins, we decided not to implant stents, considering the fact that the patient was a child and even a properly implanted stent in a few years would be too small and result in a difficult-to-manage narrowing of the iliac vein. The patient was discharged after 15 days of hospitalisation (without swelling of lower extremi-

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Endovascular mechanical thrombectomy of the inferior vena cava and iliac veins with the use of Aspirex®S device in a paediatric patient

Fig. 2. A) Control venography – patent inferior vena cava (1). B) residual stenotic lesions in the left iliac veins (2). C) Recanalisation of the left internal iliac vein (3) – there was a good outflow from pelvic veins. D) Clinical improvement after first procedure – reduction of oedema of the scrotum, penis and lower limbs. E) Final clinical effect – no swelling of the left lower limb and scrotum ties, and also of the scrotum and penis – Fig. 2E), with the recommendation of antithrombotic treatment with low-molecular-weight heparin. Control Doppler sonography performed 6 months later demonstrated good flow through the inferior vena cava and both iliac veins. Of note, there were no features of thrombophilia in laboratory investigation of the coagulation system.

DISCUSSION Deep venous thrombosis is rarely seen in children. Its prevalence is at least 100-times less frequent than that of adults. Usually neonates and adolescents are affected and thrombosis is typically associated with the use of intravenous catheters or severe morbidities (sepsis, cancer, heart disease, etc.). Anatomic abnormalities, primarily aplasia of the inferior vena cava and May-Thurner syndrome, and/ or disturbances of the coagulation syndrome can also be of an importance [1-7]. Unprovoked thrombosis in a child, such as in our patient is extremely rare. Current guidelines suggest conservative management of paediatric deep vein thrombosis. An invasive treatment can be performed only in children presenting with severe and limb-threatening thrombosis [1-3, 8]. Usually such a treatment consists of

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local administration of fibrinolytics. Recently, percutaneous mechanical thrombectomy with the use of different devices (such as AngioJet [Boston Scientific, Natick, MA, USA] or Trellis-8 [Covidien, Mansfield, MA, USA]), has been added to the armamentarium [8-10]. Our paper on the use of the Aspirex®S, to the best of our knowledge, is the first report of a successful use of this endovascular device for the treatment of deep vein thrombosis in a child. Pulmonary embolism appears to be the most important complication associated with endovascular thrombectomy of the iliac veins and the inferior vena cava. Some authors used prophylactic cava filters in patients with occluded iliac veins but patent vena cava [8, 10]. In our patient the use of such a filter was not possible, since the inferior vena cava was totally closed by the thrombus. Local administration of alteplase improves the results of venous thrombectomy in paediatric patients and is associated with acceptable low rate of bleeding adverse events (less than 20%), which are usually of minor clinical relevance [8, 10].

CONCLUSIONS Although most children presenting with deep vein thrombosis can be managed conservatively, in cases of

Paweł Latacz, Marian Simka, Tadeusz Popiela, Krzysztof Kobylarz, Janusz Skalski

severe and limb-threatening thrombosis endovascular mechanical thrombectomy combined with local intravenous administration of a fibrinolytic agent seems to be a  safe and efficient alternative. The authors declare no conflict of interest.

References 1. Naess I.A., Christiansen S.C., Romundstad P., Cannegieter S.C., Rosendaal F.R., Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5: 692-699. 2. Goldenberg N.A., Donadini M.P., Kahn S.R., Crowther M., Kenet G., Nowak-Gottl U., et al. Post-thrombotic syndrome (PTS) in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica 2010; 95: 1952-1959. 3. Raffini L., Huang Y.S., Witmer C., Feudtner C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124: 1001-1008. 4. Schneppenheim R., Greiner J. Thrombosis in infants and children. Hematology Am Soc Hematol Educ Program 2006; 2006: 86-96. 5. Young G. Diagnosis and treatment of thrombosis in children: general principles. Pediatr Blood Cancer 2006; 46: 540-546. 6. Meissner M.H., Gloviczki P., Comerota A.J., Dalsing M.C., Eklof B.G., Gillespie D.L., et al. Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2012; 55: 1449-1462. 7. Olivieri M., Kurnik K., Hoffmann F., Reiter K., Bidlingmaier C., Kuhlencordt P., et al. Ultrasound assisted endovascular thrombolysis in adolescents: 2 case reports. Pediatrics 2016; 138: e20160022. 8. Goldenberg N.A., Branchford B., Wang M., Ray C. Jr, Durham J.D., Manco-Johnson M.J. Percutaneous mechanical and pharmacomechanical thrombolysis for occlusive deep vein thrombosis of the proximal limb in adolescent subjects: findings from an institution-based prospective inception cohort study of pediatric venous thromboembolism. J Vasc Interv Radiol 2011; 22: 121-132. 9. Dandoy C.E., Kukreja K.U., Gruppo R.A., Patel M.N., Tarango C. Outcomes in children with deep vein thrombosis managed with percutaneous endovascular thrombolysis. Pediatr Radiol 2015; 45: 719-726. 10. Darbari D., Desai D., Arnaldez F., Desai K., Kallen J., Strouse J., et al. Safety and efficacy of catheter directed thrombolysis in children with deep venous thrombosis. Br J Haematol 2012; 159: 368-379.

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CCSVI IN MULTIPLE SCLEROSIS: IS IT THE END? Alessandro Rasman University of Trieste, Italy

LETTER TO EDITOR

Phlebological Review 2017; 25, 1: 91–92 DOI: https://doi.org/10.5114/pr.2017.72539 Submitted: 3.12.2017 Accepted: 14.12.2017

ADDRESS FOR CORRESPONDENCE Alessandro Rasman University of Trieste, Italy alessandro.rasman@libero.it

DEAR EDITOR, Eight years ago, Paolo Zamboni, an Italian vascular surgeon, created a firestorm in the MS community with his hypothesis that MS, believed to be an autoimmune disease, could have a vascular connection. His research has shown that patients with MS had restricted venous flow from the brain and spinal cord, a condition he named chronic cerebrospinal venous insufficiency (CCSVI). His small observational study (65 patients assessed) demonstrated that PTA of venous strictures in patients with CCSVI is safe and, especially in patients with relapsing-remitting course of the disease, positively influenced the clinical status and quality of life of MS patients [2]. Zamboni’s theory propelled wide-ranging research and the creation of a multidisciplinary society: the International Society for Neurovascular Disease to promote research on neurovascular pathologies. However, a study conducted by neurologists did not demonstrate association of CCSVI with MS [5]. MS neurologists, official gatekeepers of the disease, dismissed and even mocked Zamboni’s theory and the scientific integrity of his research. Nonetheless, thousands of Italians with MS (the incidence of MS in Italy is high) spurred by anecdotal reports of improvements spread on social media, sought such a treatment. Many patients with MS who did not improve after standard pharmacological treatment or presented with contraindications for such a therapy, were at least interested in relieving symptoms of MS or improving quality of life. They also demanded that venoplasty for MS should be covered by the Italian healthcare system, as it is for other vascular pathologies. Reported responses to CCSVI treatment were as varied as the MS population itself – some patients experienced lasting benefits in terms of renewed energy, better balance, and improved bladder control [3]. In others, early improvements vanished with time, while some patients did not improve, or even experienced complications. There were

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three fatalities associated with this treatment reported in the literature [4] MS patients called for a randomised double-blinded placebo-controlled trial performed in a similar manner to those aimed at testing new drugs. Recently a long-awaited Italian clinical trial investigating the safety and efficacy of venous percutaneous transluminal angioplasty (PTA) for the treatment of patients with multiple sclerosis (MS) has been published. Zamboni was principal investigator and senior author of this study, named “Brave Dreams” (Brain Drainage Exploited Against Multiple Sclerosis) [1]. The study wanted to provide an answer regarding the efficacy of PTA in terms of patients’ functional disability (balance, motor, sensory, visual, and bladder function, cognitive, and emotional status), which are meaningful clinical outcomes but not directly associated with inflammatory lesions detected by imaging studies. In fact, an important part of patients’ expectations, sustained and amplified by anecdotal data, has to do precisely with these functional aspects. The study confirmed a high prevalence (74%) of CCSVI in patients with MS. It also found various and complex types of venous malformations, including closed jugular valves. PTA was effective in terms of jugular blood flow restoration only in 53% of patients. According to the authors of this paper, PTA was found to be safe but clinically largely ineffective. PTA did not result in functional improvements (such as improvements in gait, balance, bladder control, fatigue, etc.) and did not reduce the mean number of new combined brain lesions detected by MRI at 12 months. Consequently, such a treatment should not be recommended in patients with MS. However, anyone who has read this seven-page long report can find a second, somewhat contradictory conclusion – that MS patients benefited from improved cerebral blood flow after angioplasty in terms of some MRI-detected lesions. Seventy-seven per cent of patients in the treatment group, 22% more than in the sham group, were free of gadolinium-enhancing lesions at 12 months. The importance of this finding was explained in the study:

Alessandro Rasman

“Gadolinium enhancement is a marker of damage to the blood-brain barrier, whose time course depends on lymphatic drainage and hence on venous drainage from the skull”. According to the authors, this should be further analysed and investigated [1]. The paper was accompanied by an editorial written by three MS neurologists, scathing in its denouncement of CCSVI, CCSVI advocacy, and the role of social media in spreading ineffective medicine. The authors of this editorial declared that the study was rigorous and definitive, and its results unequivocal [6]. But is it really so? The author declares no conflict of interest.

References 1. Zamboni P., Tesio L., Galimberti S., Massacesi L., Salvi F., D’Alessandro R., Cenni P., Galeotti R., Papini D., D’Amico R., Simi S., Valsecchi M.G., Filippini G.; Brave Dreams Research Group. Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial. JAMA Neurol 2017; doi: 10.1001/jamaneurol.2017.3825 2. Zamboni P., Galeotti R., Menegatti E., Malagoni A.M., Gianesini S., Bartolomei I., Mascoli F., Salvi F. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009; 50: 1348-58.e1-3. 3. Bavera P.M. May symptoms of chronic cerebrospinal venous insufficiency be improved by venous angioplasty? An independent 4-year follow up on 366 cases. Veins Lymphatics 2015; 4: 5400. 4. Dake M.D., Dantzker N., Bennett W.L., Cooke J.P. Endovascular correction of cerebrovenous anomalies in multiple sclerosis: A retrospective review of an uncontrolled case series. Vasc Med 2012; 17: 131-7. 5. Comi G., Battaglia M.A., Bertolotto A., Del Sette M., Ghezzi A., Malferrari G., Salvetti M., Sormani M.P., Tesio L., Stolz E., Zaratin P., Mancardi G.; CoSMoCollaborative Study Group. Observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: results from the CoSMo study. Mult Scler 2013; 19: 1508-17. 6. Green A.J., Hooman K., Josephson S.A. Combating the spread of ineffective medical procedures: a lesson learned from multiple sclerosis. JAMA Neurol 2017; doi: 10.1001/jamaneurol.2017.3066

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STILL MORE CONTROVERSIES SURROUNDING CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY EDITORIAL

Marian Simka

Phlebological Review 2017; 25, 1: 93–94 DOI: https://doi.org/10.5114/pr.2017.72540

University of Opole, Poland

Submitted: 19.12.2017 Accepted: 19.12.2017

ADDRESS FOR CORRESPONDENCE Marian Simka University of Opole Opole, Poland e-mail: mariansimka@poczta.onet.pl

This year two randomised controlled clinical trials assessing the clinical efficacy of endovascular balloon angioplasty of the internal jugular veins for the treatment of multiple sclerosis (MS) have been published [1, 2]. Both trials have been properly designed, with patients undergoing sham angioplasty in the control arm, and both failed to demonstrate clinical improvement after endovascular procedure in terms of relief of clinical symptoms of MS. These results were similar to a previously published small randomised controlled trial that has also demonstrated no clinical benefit of such a procedure in comparison with a sham group [3]. Of note, both trials revealed overall clinical improvement in MS patients, in the treatment and sham arms alike, thus the improvements reported in a number of open-label studies [4-6] probably resulted from placebo effect, which in MS patients is probably more pronounced than in other diseases. Still, despite discouraging results of the above-mentioned studies, it seems that the research on chronic cerebrospinal venous insufficiency (CCSVI) will continue, but with the focus on other aspects of neurovascular pathology. In contrast to some negative surveys that suggested that such an entity as CCSVI does not exist at all [7], both trials clearly confirmed compromised outflow through internal jugular veins in MS patients, albeit not in all individuals. The revealed prevalence of pathological internal jugular veins was similar to that found by functional MR studies [8,9]. Moreover, another recently published study demonstrated that an increased collateral outflow through the facial vein, which is a hallmark of an occluded internal jugular vein, was associated with neurodegenerative lesions in MS patients [10]. Since a higher prevalence of CCSVI has also been reported in patients with other neurodegenerative conditions, such as Parkinson’s and Meniere diseases, it is likely that CCSVI is actually associated with neurodegeneration and not with MS as has been

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claimed in Zamboni’s early papers [11, 12]. Whether this association of CCSVI with neurodegeneration is causative, and which of the two is primary, should be elucidated by future studies [13, 14] The author declares no conflict of interest.

References 1. Zamboni P, Tesio L, Galimberti S, Massacesi L., Salvi F., D’Alessandro R., Cenni P., Galeotti R., Papini D., D’Amico R., Simi S., Valsecchi M.G., Filippini G. Brave Dreams Research Group. Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial. JAMA Neurol 2017; doi: 10.1001/jamaneurol.2017.3825 2. Traboulsee A., Machan L., Girard M., et al. Venoplasty of chronic cerebral spinal venous insufficiency to improve MS patient reported outcomes is not superior to sham treatment at week 2 or week 12. J Neurol Sci 2017; 381 (suppl.): 1066. 3. Siddiqui A.H., Zivadinov R., Benedict R.H., et al. Prospective randomized trial of venous angioplasty in MS (PREMiSe). Neurology 2014; 83: 441-449. 4. Ludyga T., Kazibudzki M., Latacz P., et al. Early results of a prospective open-label study on endovascular treatments for chronic cerebrospinal venous insufficiency in the patients with associated multiple sclerosis. Phlebol Rev 2011; 19: 9-14. 5. Denislic M., Milosevic Z., Zorc M., Mendiz O., Zuran I. Disability caused by multiple sclerosis is associated with the number of extracranial venous stenoses: possible improvement by venous angioplasty. Results of a prospective study. Phlebology 2013; 28: 353-360. 6. Simka M., Janas P., Ludyga T., et al. Endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. Vasc Dis Manag 2012; 9: 149-154. 7. Comi G., Battaglia M.A., Bertolotto A., Del Sette M., Ghezzi A., Malferrari G., Salvetti M., Sormani M.P., Tesio L., Stolz E., Mancardi G. Italian multicentre observational study of the prevalence of CCSVI in multiple sclerosis (CoSMo study): rationale, design, and methodology. Neurol Sci 2013; 34: 1297-1307.

Marian Simka

8. Haacke E.M., Feng W., Utriainen D., Trifan G., Wu Z., Latif Z., Katkuri Y., Hewett J., Hubbard D. Patients with multiple sclerosis with structural venous abnormalities on MR imaging exhibit an abnormal flow distribution of the internal jugular veins. J Vasc Interv Radiol 2012; 23: 60-8. e1-3. 9. Simka M. What is the relationship between chronic cerebrospinal venous insufficiency and multiple sclerosis? Rev Vasc Med 2013; 1: 66-70. 10. Jakimovski D., Marr K., Mancini M., et al. Global and regional brain atrophy is associated with low or retrograde facial vein flow in multiple sclerosis. Veins Lymphatics 2017; 6: 6976. 11. Zamboni P., Galeotti R., Menegatti E., Malagoni A.M., Tacconi G., Dallâ&#x20AC;&#x2122;Ara S., Bartolomei I., Salvi F. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009; 80: 392-399. 12. Zamboni P., Galeotti R. The chronic cerebrospinal venous insufficiency syndrome. Phlebology 2010; 25: 269-279. 13. Simka M., Ludyga T., Latacz P., Kazibudzki M., Majewski E., Zaniewski M. Chronic cerebrospinal venous insufficiency is unlikely to be aÂ direct trigger of multiple sclerosis. Mult Scler Rel Disord 2013; 2: 334-339. 14. Rasman A. CCSVI in multiple sclerosis: is it the end? Phlebol Rev 2017; 25: 91-92.

Phlebological Review 2017

Instructions for authors Phlebological Review is the official journal of the Polish Phlebological Society and an international journal that features peer-reviewed articles on research related to venous and lymphatic diseases. The journal also publishes papers on related topics such as molecular biology, biochemistry, genetics, biophysics, medical technology and imaging dealing with disorders of the veins and lymphatic vessels. All of the articles in Phlebological Review are published on an open access basis. Published articles are available (full text) in PDF and HTML format. Papers should be submitted to the Editorial Office on-line by the Editorial System: www.editorialsystem.com/pr

Preparation of manuscripts

Articles must be written in English with American or British spelling used consistently throughout. Authors not entirely familiar with English are advised to have their style corrected by professional language editors or native English speakers. • The length of original articles should not exceed 20 printed pages including text, illustrations, tables, and references. •E ach article should contain a structured abstract (200-250 words). • The manuscript body should be organized in a standard form with separate sections: Introduction, Material and methods, Results, Discussion, and References. Review articles should be divided into sections and subsections as appropriate without numbering. • All dimensions and measurements must be given in the metric system. • Th e source of any drug and special reagent should be identified. • Particular attention needs to be paid to the selection of appropriate analysis of data and the results of statistical tests should be incorporated in the Results section. • The nomenclature used should conform to the current edition of the Nomina Anatomica or Nomina Anatomica Veterinaria. • Acknowledgements should be made in a separate sheet following Discussion and before References. These should contain a list of dedications, acknowledgements, and funding sources. •L egends of figures and tables should be prepared as a separate file. • Th e editor reserves the right to make corrections.

Tables

• Tables numbered in Roman numerals require a brief but descriptive heading. • The major divisions of the table should be indicated by horizontal rules. • Explanatory matter should be included in footnotes, indicated in the body of the table in order of their appearance. • Tables must not duplicate material in the text or in illustrations. • Tables must be prepared as a separate file.

Illustrations

All figures should be supplied electronically at a resolution of 300dpi in all standard formats (tiff, jpg, Adobe Photoshop, Corel Draw, and EPS). Name your figure files with “Fig” and the figure number, e.g., Fig1.tif • The maximum figure size is 84 mm or 174 mm for use in a single or double column width, respectively. • When possible, group several illustrations in one block for reproduction. Like all other figures, the block should be prepared within a rectangular frame to fit within a single or double column width of 84 and 174 mm, respectively, and a maximum page height of 226 mm. • Each figure should include the scale magnification bar; do not use magnification factors in the figure legends. • All figures, whether photographs, graphs or diagrams, should be numbered using Arabic numerals and cited in the text in consecutive numerical order.

References

The list of references (written on a separate page) should include only those publications that are cited in the text. Avoid citation of aca-

Phlebological Review 2017

demic books, manuals and atlases. References must be numbered consecutively. References should be given in square brackets and the consecutive number, e.g. [3, 4, 6-12]. References should be written as follows: Journal papers: initials and names of all authors, full title of the paper, journal abbreviation (according to Index Medicus), year of publication, volume (in Arabic numerals), first and last page (examples below): 1. Valverde F. The organization of area 18 in the monkey. Anat Embryol 1978; 154: 305-334. 2. Uray N.J., Gona A.G. Calbindin immunoreactivity in the auricular lobe and interauricular granular band of the cerebellum in bullfrogs. Brain Behav Evol 1999; 53: 10-19. Book and monographs: initials and names of all authors, full title, edition, publisher, place, year (examples below): 1. Pollack R.S. Tumor surgery of the head and neck. Karger, Basel 1975. 2. Amaral D.G., Price J.L., Pitkänen A., Carmichael S.T. Anatomical organization of the primate amygdaloid complex. In: Aggleton JP (ed.). The amygdala. Wiley-Liss, New York 1992; 1-66. Reference to articles that are accepted for publication may be cited as “in press” or Epub.

Ethical requirements

When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000 (concerning the ethical principles for the medical community and forbidding releasing the name of the patient, initials or the hospital evidence number) and with the ethical standards of the responsible committee on human experimentation (institutional and national). Information regarding the ethical committee approval for conducting the research and the informed consent of patients to participating in the studies should be included in the Methods section of those articles, in which the diagnostic intervention or the treatment result from non-routine procedures. The authors presenting case studies are obligated not to disclose patients’ personal data. Regarding photographs, in case of any doubt that the picture inadequately protects the patient’s anonymity his consent is required for publication.

Conflict of interest

Authors are expected to describe sources of the research funding, a role of the potential sponsor in planning, executing and analysis of the study, and the influence (bias) the funding organization had on the content of the article. Other relationships (such as employment, consultancies, stock ownership, honoraria, paid expert testimony) providing potential sources of conflict of interest in relation to the submitted article should also be revealed.

Review process

Received manuscripts are first examined by the Phlebological Review editors. Manuscripts with insufficient priority for publication are rejected promptly. Incomplete submissions or manuscripts not prepared in the advised style will not be sent for a peer review until the correct and complete submission has been provided. The registered manuscripts are sent to 2-3 independent experts for scientific evaluation. We encourage authors to suggest the names of possible reviewers in the Editorial System, but we reserve the right of final selection. Submitted papers are accepted for publication after a positive opinion of the independent reviewers. The Polish Phlebological Society acquires all copyrights, on an exclusive basis, to manuscripts published, including the right to publish in print, using electronic carriers or others, and on the Internet. Abstracts may be published without the Publisher’s permission.